Acquired immune deficiency syndrome (AIDS), caused by infection of human immunodeficiency virus (HIV), results in more than 2 million human death every year and is still a global social concern nowadays. Although more than 30 years has pasted since the first report of AIDS, the cures or vaccines are remained elusive. To date, an arsenal of 28 new chemical entity drugs have been approved by FDA, but none of them could eliminate the virus completely. Although the highly active antiretroviral therapies (HAART) could significantly reduce the morbidity and mortality of AIDS, the severe side effects and drug resistance along with the long-term use of approved drugs result in the suspending of treatment. So, there is an urgent the development of novel inhibitors with improved tolerability and resistance profiles.
Reverse transcriptase (RT) plays essential roles in the life cycle of HIV-1 virus and it is responsible for reverse transcription of viral single-stranded RNA into double stranded viral DNA. For the well solved 3D structure and a well-known action mechanism, RT has been regarded as an attractive target for years. According to the action mechanism, RT inhibitors are divided into two classes: nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), while NNRTIs attract comprehensive attentions for their high potency and low toxicity. However, for the error prone of replication, drug-resistant mutants with reduced susceptibility to NNRTIs have emerged rapidly and lead to the failure of clinical drugs, so considerable efforts have been applied towards finding novel inhibitors with anti-resistance profiles.
Diarylpyrimidine (DAPY) derivatives are second generation NNRTIs with high potency, low toxicity and promising anti-resistance profiles, with two compounds (Etravirine and Rilpivirine) have been marketed. But for the intrinsic specificity, DAPY derivatives demonstrate low solubility, which lead to poor bioavailability. Thus, it is necessary to discover new inhibitors with potent anti-drug resistance profiles, and favorable oral bioavailability.
